Characterization of two classes of small molecule inhibitors of Arp2/3 complex

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Abstract
The actin cytoskeleton is dynamic and plays a critical role in several cell biological processes such as cell adhesion, migration and endocytosis. In addition, several pathogens exploit this system to invade and survive within host cells. The Arp2/3 complex nucleates actin filaments and has a unique property to form branched actin networks. In this study, Nolen et al. describe the generation of two types of small molecules that bind to different sites on the Arp2/3 complex and inhibit its actin nucleating activity in vitro and in vivo. These inhibitors provide a powerful approach to study Arp2/3 complex-mediated actin reorganization events in living cells. The actin cytoskeleton plays a critical role in cell biological processes such as cell adhesion, migration and endocytosis. Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movement. Two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments are now described; these inhibitors provide a powerful approach for studying the Arp2/3 complex in living cells. Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements1. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.